SUMMARY The unprecedented COVID-19 global health crisis is fueled by the absence of an effective vaccine and no specific antiviral drugs. Consequently, major research efforts have focused on identifying efficacious therapies. The most effective short-term solution is repurposing and repositioning of approved drugs or clinical-stage drug candidates, as this approach shortens the time to the clinic. Furthermore, as there are no drugs against any zoonotic coronaviruses associated with human respiratory infections, pan-coronavirus drug regimens are vital to counter future outbreaks. To best address this urgency, a drug development Accelerator has been established as a formal partnership between our NIH Center of Excellence in Translational Research (CETR) and Merck and Co., Inc., a global leader in the discovery and development of antiviral drugs. The CETR program, which is focused on novel and repositioned drugs against high-threat bacterial infections, provides a comprehensive platform for drug discovery. Merck brings a full complement of approved antiviral drugs and advanced candidates for repurposing and repositioning, with an emphasis on novel nucleoside and protease inhibitors. Firstly, small molecule compounds representing both FDA approved drugs and clinical stage drug candidates discovered against other viruses will be evaluated in viral cytopathic and neutralization assays to assess inhibition of SARS- CoV-2. Lead candidates will be assessed for EC50/90/CC50 values, ADME pharmacokinetics, and safety to determine their potential for immediate use in therapy. If data supports a robust therapeutic window, then repurposed compound(s) will be submitted for an IND under FDA EUA. A rodent model utilizing SARS-CoV-2 infection will be used to assess in vivo PK/PD parameters supporting clinical dose ranging and safety margins. Secondly, a pan-coronavirus drug development candidate will be identified from either drug repositioning or from Merck?s focused compound libraries for existing antiviral classes discovered against other conserved viral targets, as well as new lead series to host and viral targets representing >65 mechanisms of action. These compounds will be screened in a high throughput virus challenge assay. SAR will benefit from the multi-million compound Merck sample collection via in silico substructure and similarity searches. Lead compounds will be assessed for robust in vivo therapeutic efficacy against SARS-CoV-2; metabolic stability, toxicity, ADME, rodent tolerability; pharmacologic properties consistent with QD or BID dosing, and acceptable safety margins supportive of initiation of first in human clinical studies. The ultimate goal is the identification of development candidates that can enter preclinical IND enabling safety derisking studies. This is an unprecedented public-private partnership for drug discovery The goal of this drug Accelerator is to identify a repurposed compound(s) that can treat COVID-19 patients within 4-6 months and by the end of Year 2, identify candidates with pan-coronavirus efficacy that can enter preclinical IND-enabling and derisking studies.